Other Bone Remodeling Molecules Proteins

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 Other Bone Remodeling Molecules Proteins Background

Bone is one of the most complex organs in the body, for all its simplicity of function. Bone's function can be summed up into two tasks: structurally support soft tissue and maintain a mineral reserve. Despite it being one of the longest studied tissue systems, our understanding of how bones accomplish these two tasks is still riddled with mysteries. There are three main reasons why a better understanding of bone biology exceeds current scientific understanding.

First, while one component of bone—the mineral portion of the matrix - is easy to detect and study using x-rays, the other two components of bone—the organic matrix and the cells—are extremely difficult to observe. The dense, mineral nature of bone effectively shields the cells from view. Osteocytes, the most abundant bone cells, are particularly difficult to study since they are completely encapsulated within mineralized matrix. Due to the mineral content, a histological slide of bone often takes at least one month to prepare, as compared to a few days for soft tissue, and there are often many of artifacts created in the process. Magnetic resonance imaging (MRI) and nano-indentation technologies now offer new insights into bone micro structure and composition, but MRI only provides vague assessments of the marrow's status and nano-indentation only provides another assessment of mechanical strength. Additionally, not all the cells are visible under light microscopy; bone-lining cells are so flat that they only show up as only a thin, faint line on most slides and frequently go unseen in the visually busy areas of the bone surface.

Secondly, bone remodeling also operates on longer time scales than other tissues. The complexity and toughness of bone means that remodeling and regular turnover takes months, as opposed to days like in most tissues. Basic turnover requires more signals over a longer time and spatial scale than other tissues. There is also a substantial delay between the start of bone pathologies and the moment symptoms appear, which usually results in most of the evidence of a disease's mechanisms of action being gone before a biopsy can be taken.

A third reason why bone proves difficult to understand is the complex cellular interactions required for any change to the bone. Bone remodeling relies heavily on spatio-temporal patterns to guide the function of its cells, possibly due to the long timespans of the remodeling process. Also, since the function of bone is a balance between the release of calcium to maintain serum ion concentrations and the sequestering of calcium for bone strength, there are multiple physiological balances constantly interacting between a many different of cell types. This complexity makes simple cause and effect models imprecise and inaccurate in many cases, and the lack of accurate models is a major problem plaguing in medical treatment and therapy design.


Bone biology

Bone by its nature is dynamic. It undergoes constant structural changes as a result of adaptation and bone remodeling. This dynamic process is referred to as the Wolff’s law named after the German anatomist Julius Wolff, who first noticed this phenomenon in 1982. The purpose of bone remodeling is to prevent the accumulation of damage, adapt the internal architecture to external loads and provide a way for the body to alter the balance of the essential minerals by accessing the stores of calcium and phosphate. To effectively study the bone remodeling phenomenon, it is important to know the components of the bone and the bone remodeling process. Since the focus of this project is on the lumbar region. The outer dense bone is called the cortical bone and the inner porous bone is called the cancellous bone.

The bone remodeling process involves the coordinated actions of different bone cells, i.e., osteoclasts, osteoblasts, osteocytes and bone lining cells at each stage. Osteoblasts have a single eccentric nucleus, and are responsible for the bone formation. Osteoclasts are multi-nucleated cells responsible for bone resorption or removing old bone materials. Osteoblasts and osteoclasts together are called the Basic Multicellular Unit (BMU). During bone formation some of the osteoblasts get trapped in the matrix that they secrete and become Osteocytes. Another type of cells that cover the surface are called bone lining cells. Lining cells are considered to be quiescent osteoblasts. Osteocytes connect to each other and to the lining cells through narrow channels called the canaliculi. The osteocytes, with their interconnected cellular network, play an important role in communication and transportation between cells within the bone matrix. Bone goes through a continuous process of modeling in younger animals. In humans, it reaches a peak mass at approximately 30 years of age. The bone formation and the bone resorption processes are almost balanced in adults, hence there is no significant change in the bone mass. However, the internal micro-architecture keeps changing under the influence of loads. Bone remodeling is a cyclic process involving five stages: quiescence, activation, resorption, reversal, and formation. The balance between bone resorption and formation determines the bone mineral content and the micro-architecture.

Bone remodeling occurs at multiple spatially and temporally discrete sites. It happens in both the cancellous bone and the cortical bone. Normally 80% of the bone surface is quiescent with respect to bone remodeling. Activation requires recruitment of osteoclasts, a means for them to gain access to the bone and a mechanism to attach to the bone surface. Activation is a function of age, sex and metabolic state. It occurs partly at random and partly in response to the biomechanical requirement. After coming in contact with the bone, the osteoclasts begin to resorb the bone. It is referred to as Howship’s lacuna in cancellous bone and as cutting cone in cortial bone. The resorption cavity has a characteristic shape and dimension. The resorption cavity grows at a rate of 5-10 µm/day perpendicular to the surface and 20-40 µm/day parallel to the surface. After the resorption ends, it enters a reversal phase. The rough surface of the resorption cavity is smoothed and a thin layer of highly mineralized matrix is laid down, preparing the surface for bone formation. Once the surface is ready, osteoblast cells are recruited. This phase has two parts, matrix synthesis and mineralization. Matrix synthesis precedes mineralization. The newly laid unmineralized bone matrix is called osteoid. This separates the osteoblasts and the newly mineralized bone. Synthesis terminates after the cavity is filled. Mineralization continues slowly until the osteoid seam disappears. The osteoblasts that remain on the surface transform into lining cells. Bone adapts its structure much more readily during growth than after skeletal maturation. During modeling there is no need for activation of the surface since it is continuously active from earliest embryonic stage until growth ceases. Whereas in the adult bone, the adaptive change to occur, the quiescent surface needs activation.